Constitutive Activation of STAT5A Promotes Human Hematopoietic Stem Cell Self-renewal and Erythroid Differentiation

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2004 Sep 9

PMID 15353555

Citations 55

Authors

Jan Jacob Schuringa

Ki Young Chung

Giovanni Morrone

Malcolm A S Moore

Affiliations

Soon will be listed here.

Abstract

Activation of the transcription factor signal transducer and activator of transcription (STAT)5 is involved in various aspects of hematopoiesis, affecting cell proliferation, differentiation, and cell survival. Constitutive activation of STAT5 has also been associated with leukemic transformation. We overexpressed the constitutively active mutant STAT5A(1*6) in human cord blood CD34+ cells and evaluated the effects on the hematopoietic potential of stem cells in a variety of in vitro and in vivo systems. The observed phenotypic changes were correlated with differential gene expression patterns induced by STAT5A(1*6). Our data indicate that a persistent activation of STAT5A in human hematopoietic stem and progenitor cells results in their enhanced self-renewal and diverts differentiation to the erythroid lineage.

Citing Articles

Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.

Williams M, Wang X, Bastos H, Grondys-Kotarba G, Wu Q, Jin S Blood Adv. 2024; 9(2):291-309.

PMID: 39374575 PMC: 7617191. DOI: 10.1182/bloodadvances.2024014046.

Unraveling Hematotoxicity of α-Amanitin in Cultured Hematopoietic Cells.

Hof W, Visser M, de Jong J, Rajasekar M, Schuringa J, de Graaf I Toxins (Basel). 2024; 16(1).

PMID: 38276537 PMC: 10820516. DOI: 10.3390/toxins16010061.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Kan W, Dhagat U, Kaufmann K, Hercus T, Nero T, Zeng A Cancer Discov. 2023; 13(8):1922-1947.

PMID: 37191437 PMC: 10401075. DOI: 10.1158/2159-8290.CD-22-1396.

Influence of Long Non-Coding RNA in the Regulation of Cancer Stem Cell Signaling Pathways.

Sonawala K, Ramalingam S, Sellamuthu I Cells. 2022; 11(21).

PMID: 36359888 PMC: 9656902. DOI: 10.3390/cells11213492.

Expression of RUNX1-JAK2 in Human Induced Pluripotent Stem Cell-Derived Hematopoietic Cells Activates the JAK-STAT and MYC Pathways.

Fortschegger K, Husa A, Schinnerl D, Nebral K, Strehl S Int J Mol Sci. 2021; 22(14).

PMID: 34299194 PMC: 8304339. DOI: 10.3390/ijms22147576.

References

Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui A, Kitamura T . STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J. 1999; 18(17):4754-65. PMC: 1171548. DOI: 10.1093/emboj/18.17.4754. View

Socolovsky M, Fallon A, Wang S, Brugnara C, Lodish H . Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Cell. 1999; 98(2):181-91. DOI: 10.1016/s0092-8674(00)81013-2. View

Schuringa J, Wu K, Morrone G, Moore M . Enforced activation of STAT5A facilitates the generation of embryonic stem-derived hematopoietic stem cells that contribute to hematopoiesis in vivo. Stem Cells. 2004; 22(7):1191-204. DOI: 10.1634/stemcells.2004-0033. View

Park I, Qian D, Kiel M, Becker M, Pihalja M, Weissman I . Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003; 423(6937):302-5. DOI: 10.1038/nature01587. View

Reya T, Duncan A, Ailles L, Domen J, Scherer D, Willert K . A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003; 423(6938):409-14. DOI: 10.1038/nature01593. View

Spiekermann K, Bagrintseva K, Schwab R, Schmieja K, Hiddemann W . Overexpression and constitutive activation of FLT3 induces STAT5 activation in primary acute myeloid leukemia blast cells. Clin Cancer Res. 2003; 9(6):2140-50. View

Hirokawa S, Sato H, Kato I, Kudo A . EBF-regulating Pax5 transcription is enhanced by STAT5 in the early stage of B cells. Eur J Immunol. 2003; 33(7):1824-9. DOI: 10.1002/eji.200323974. View

Komura E, Chagraoui H, de Mas V, Blanchet B, De Sepulveda P, Larbret F . Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression. Exp Hematol. 2003; 31(7):622-30. DOI: 10.1016/s0301-472x(03)00085-7. View

Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Minden M . A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367(6464):645-8. DOI: 10.1038/367645a0. View

10.

Gouilleux-Gruart V, Gouilleux F, Desaint C, Claisse J, Capiod J, Delobel J . STAT-related transcription factors are constitutively activated in peripheral blood cells from acute leukemia patients. Blood. 1996; 87(5):1692-7. View

11.

Szilvassy S, Weller K, Lin W, Sharma A, Ho A, Tsukamoto A . Leukemia inhibitory factor upregulates cytokine expression by a murine stromal cell line enabling the maintenance of highly enriched competitive repopulating stem cells. Blood. 1996; 87(11):4618-28. View

12.

Shuai K, Halpern J, Ten Hoeve J, Rao X, Sawyers C . Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene. 1996; 13(2):247-54. View

13.

Bonnet D, Dick J . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997; 3(7):730-7. DOI: 10.1038/nm0797-730. View

14.

Chai S, Nichols G, Rothman P . Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol. 1997; 159(10):4720-8. View

15.

Kondo M, Weissman I, Akashi K . Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997; 91(5):661-72. DOI: 10.1016/s0092-8674(00)80453-5. View

16.

Onishi M, Nosaka T, Misawa K, Mui A, Gorman D, McMahon M . Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol. 1998; 18(7):3871-9. PMC: 108971. DOI: 10.1128/MCB.18.7.3871. View

17.

Xia Z, Baer M, Block A, Baumann H, Wetzler M . Expression of signal transducers and activators of transcription proteins in acute myeloid leukemia blasts. Cancer Res. 1998; 58(14):3173-80. View

18.

Chida D, Miura O, Yoshimura A, Miyajima A . Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression. Blood. 1999; 93(5):1567-78. View

19.

Matikainen S, Sareneva T, Ronni T, Lehtonen A, Koskinen P, Julkunen I . Interferon-alpha activates multiple STAT proteins and upregulates proliferation-associated IL-2Ralpha, c-myc, and pim-1 genes in human T cells. Blood. 1999; 93(6):1980-91. View

20.

Piacibello W, Sanavio F, Severino A, Dane A, Gammaitoni L, Fagioli F . Engraftment in nonobese diabetic severe combined immunodeficient mice of human CD34(+) cord blood cells after ex vivo expansion: evidence for the amplification and self-renewal of repopulating stem cells. Blood. 1999; 93(11):3736-49. View